Chronic obstructive pulmonary disease (COPD) encompasses several clinical syndromes, most notably emphysema and chronic bronchitis. It is a major unmet medical need in the United States and worldwide and, in western society, is impressively associated with cigarette smoke (CS) exposure. We hypothesized that CS dysregulates RLH signaling, and the dysregulation of RLH signaling plays an important role in CS-induced inflammation and remodeling responses. To address this, we focused additional investigations on the molecules that regulate MAVS, especially mitochondrial molecules, because MAVS is bound to the mitochondrial outer membrane and its localization on mitochondria is critical for the proper functioning of MAVS. Intriguingly, our preliminary studies from our CS-induced murine emphysema model revealed that a novel mitochondrial molecule, nucleotide binding domain and leucine rich repeat containing protein X1 (NLRX1) that interacts with MAVS and inhibits MAVS-mediated production of type I interferons (IFNs) and NF?B signaling, was significantly suppressed in CS-exposed lungs. In addition, CS-induced significant activation of inflammasome(s) and the consequent interleukin1? (IL1?) and IL18 activation, induction of type I IFNs and pulmonary inflammation and emphysematous destruction; these responses were exaggerated in the absence of NLRX1, while ameliorated in the absence of MAVS. Importantly, the expression of NLRX1 is suppressed in lungs from three different human COPD cohorts. Furthermore, this suppression shows impressive correlation with the degree of airflow limitation, a hallmark of COPD, and other clinical variables related to disease severity. This constellation of findings has led us to the following multipart hypothesis and specific aims; Aim #1. Define the roles of MAVS and NLRX1 in CS-induced activation of inflammasome(s), induction of type I IFNs and pulmonary inflammatory and remodeling responses; Aim #2. Characterize the effects of CS on the expression of NLRX1 in mice, the alteration of the expression of NLRX1 in patients with COPD, and the role of NLRX1 in the inflammasome activation in macrophages; Aim #3. Determine the reactive oxygen species (ROS)dependent inhibition of NLRX1 against the assembly of inflammasome complex on MAVS in macrophages in vitro; Aim #4. Determine if restoring NLRX1 in vivo ameliorates CS-induced activation of inflammasome(s), induction of type I IFNs and pulmonary inflammatory and remodeling responses. With successful accomplishment of this project, we will define the roles of novel mitochondrial molecules called NLRX1 and MAVS in the development of COPD. In addition, we will test the possibility that interventions that restore suppressed NLRX1 or modulate this pathway may have therapeutic potential to ameliorate rapid decline of lung function as well as enhanced pulmonary inflammation in smokers and patients with COPD.